Rheumatoid arthritis (RA) is a chronic inflammatory disease that manifests as painful and swollen joints and subcutaneous nodules, among other symptoms. The pathophysiology of the disease is autoimmune in nature and is believed to arise from genetic susceptibility coupled with specific environmental exposures. In RA, the synovium is the primary site of inflammation; synovial macrophages increase significantly in patients with RA, relative to normal synovium, and activated synovial macrophages are largely responsible for propagating inflammation and tissue destruction as they are the main producers of pro-inflammatory cytokines such as TNF-?. Presently, there is not a cure for RA. A relatively recent breakthrough has been the introduction of biologics such as anti-TNF-? antibodies, as TNF-? plays a key role in the development and progression of RA. Anti-TNF-? biologics are proven effective in treating patients previously unresponsive to other anti-rheumatic therapies, but not without limitations. Small-interfering RNA (siRNA), e.g. TNF-? siRNA, offers an attractive alternative to controlling pro-inflammatory cytokines at the level of gene expression. We recently developed a new TNF-? siRNA solid-lipid nanoparticle formulation that is efficacious in treating RA in a mouse model of collagen antibody-induced arthritis. However, a key issue with siRNA therapy is the toxicity associated with the acute inflammatory response induced by the siRNA. Our long-term goal is to develop a safe and effective siRNA-based RA therapy. Herein we propose an innovative approach to minimize or eliminate the acute inflammatory response associated with siRNA therapy by including an anti-inflammatory compound into our TNF-? siRNA solid-lipid nanoparticles. We hypothesize that the proposed new TNF-? siRNA solid-lipid nanoparticles will not only address the acute inflammatory response associated with siRNA therapy, but also be more efficacious than our nanoparticles incorporated with TNF-? siRNA alone in controlling RA in a mouse model. We propose two specific aims to test this hypothesis: i) to identify the extent to which encapsulation of an anti-inflammatory compound into our TNF-? siRNA solid-lipid nanoparticles will reduce the acute pro- inflammatory response induced by the siRNA-nanoparticles in a mouse model; ii) to identify the extent to which our new TNF-? siRNA solid-lipid nanoparticles will control arthritis in a mouse model of collagen-induced arthritis. The primary innovation of this project is the encapsulation of a known anti-inflammatory compound into TNF-? siRNA nanoparticles i) to systemically inhibit the acute pro-inflammatory response associated with siRNA therapy, and ii) locally at the chronic inflammation sites to enhance the efficacy of the TNF-? siRNA. Our project is significant because the proposed co-delivery approach, when proven successful, is expected to afford a new and effective treatment to RA and potentially other chronic inflammatory conditions as well.